Agonists

Endothelin

The endothelins are the strongest vasoconstrictors known, acting to maintain vascular tone. In addition, they have multiple effects on disparate systems: such as sodium balance, heart rhythm, neural development, and vascular endothelial proliferation. Three 21-residue endothelin peptides with two disulfide bridges are encoded by three genes and differ somewhat in their physiological roles.1 Thus far only two receptors, ETA and ETB, have been described. These receptors are linked to a Gq protein. We offer very pure human endothelins 1,2, and 3 as receptor agonists. Two linear peptides that lack disulfide bridges, BQ-3020 and (Ala 1,3,11,15)-Endothelin 1, are specific agonists for the ETB receptor.

Endothelins have been highly conserved in evolution. Venom from the Atractaspis engaddensis viper contains three isototoxins that are highly analogous to endothelins and bind to cardiac endothelin receptors. A bite from this snake can disrupt heart rhythm and constrict coronary vessels enough to cause death within minutes. One venom isoform, sarafotoxin S6b is an ETA agonist, while isoform sarafotoxin S6c is an ETB agonist.

Endothelin-1 (ET-1) is a vasoconstrictor, which is increased in plasma and explants of patients with uterine leiomyomas. Thus, uterine fibroids are linked to increased ET-1 levels and hypertension, which is worsened by hypoxic condtions. ET-1 RNAi and Endostar are capable of preventing the progression and invasiveness of PC-3 (prostate cancer) cells. The plasma levels of this peptide are increased in patients with atrial septal defect (ASD), and these levels might help in diagnosis of closure defects. The plasma level of ET-1 is also higher in patients with end-stage renal disease (ESRD), and this is linked to gradual worsening of pulmonary function tests.Potent agonist for ETA and ETB endothelin receptors. Induces the production of hypoxia-inducible factor 1α, and, thus, the production of VEGF.

Endothelin-2 (ET-2) has a regulatory role in multiple cancer types, such as breast and clear cell renal cell carcinoma (ccRCC). It is overexpressed during early stages of non-metastasized ccRCC, and is thought have a role in the progression of the same. It is a hypoxia-related factor, and might have protective action against cell death in neuronal diseases. It acts as a ligand for ET-A and ET-B receptors, which results in vasoconstriction. A985 polymorphism in this gene is thought play a protective role in cardiovascular diseases, but it acts as a susceptibility factor in atrial fibrillation in hypertrophic cardiomyopathy patients. In neural retina, it suppresses angiogenesis, and facilitates the tip cell state in endothelial cells.

Endothelin 3 (ET3) is a vasoconstrictor that acts in a paracrine and autocrine manner, and in intestinal lamina propria causes the degranulation of mast cells. It results in the release of ions from intestinal epithelial cells. In acute and chronic intestinal inflammation, it is overexpressed. It is also up-regulated in colon carcinoma, where it supports cell proliferation and survival. It might be involved in colon homeostasis, and is essential for the survival and proliferation of goblet cells. In mice, it is essential for the development of pigment cells derived from neural crest (NC). Its expression is de-regulated in metastatic melanoma.Potent vasoconstrictor from vascular endothelial cells; preferred agonist for ETB endothelin receptors. Induces the production of VEGF.